1. Field of the Invention
The present invention relates to a novel purinylpyridinylamino-2,4-difluorophenyl sulfonamide derivative, a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition with an inhibitory activity against Raf kinase, containing the same as an active ingredient.
2. Description of the Related Art
Cancer, as one of the most common diseases people can contract, has becoming a major cause of death. Many research groups have invested a large sum of research funds over recent decades into development of effective treatments for cancer. However, only a few anticancer treatments are proved to be effective, but there is rarely an effective treatment for most of cancers.
Most of the compounds commonly used for chemotherapy up to the present have a risk of side effects and tolerance. One of the side effects is that currently used anticancer treatments cannot act on cancer cells selectively and exclusively from healthy cells, causing toxicity to normal cells. As an alternative to developing an anticancer drug or treatment with less side effects yet higher curative value, there needs an anticancer drug or treatment that can act on metabolic pathway or the constituents of the pathway, i.e. the targets which are expressed in cancer cells but not or hardly expressed in healthy cells. Protein kinase is an enzyme catalyzing the phosphorylation of a hydroxyl group of a particular protein residue, e.g., tyrosine, serine, or threonine residue. The phosphorylation can activate the function of protein, and protein kinase plays a key role in regulating a multiple cellular processes including particular metabolism, cell proliferation, cell differentiation, cell migration, or cell survival. Among the various cellular actions involving the activity of protein kinase, particular pathways are considered a suitable target for the treatment of cancer-related diseases and other diseases. In this regard, one of the objectives of the present invention is to provide a composition that has anticancer activity and functions particularly in connection with the kinase.
Ras/Raf/MEK/ERK protein kinase signaling pathway plays a very important role in regulating the cellular functions and is involved, specifically, in cell proliferation, cell differentiation, cell survival, and angiogenesis [Biology of the Cell, 2001, 93, 53˜62]. In the signaling pathway, if guanosine triphosphate (GTP) is conjugated with Ras protein, the Raf protein in the plasma membrane is phosphorylated and activated. The activated Raf protein phosphorylates and activates MEK protein and the MEK protein phosphorylates and activates ERK protein. Accordingly, translocation of the activated ERK from cytoplasm to nucleus results in phosphorylating and regulating the activities of the transcription factors such as Elk-1 and Myc.
Raf protooncogene is serine/threonine (Ser/Thr) protein kinase, which is a substance transmitting the signals sent from the growth factor receptor activated in cell membrane to the transcription factor in nucleus. The activation of the Raf protein is accompanied by the phosphorylation of tyrosine, serine, and threonine residues of the Raf protein. The direct phosphorylation by the receptor tyrosine kinase or the phosphorylation by the protein phosphorylation enzymes regulated by the receptors is believed to be the mechanism of the Raf activation. In the case of the regulation by the receptors, Ras is involved in the activation of Raf. The signals arrived at Raf are transmitted back to the nucleus through the signaling pathway connected to the Raf/MEK/ERK protein kinase. In the signaling pathway, a series of kinases are arranged lengthwise to transmit signals, which performs an essential role in growth and differentiation of cells [Nature Rev. Mol. Cell. Biol., 2004, 5, 875˜885].
In this way, Raf functions as a major propagator of the Ras function. Therefore, a theoretical background for anticancer treatments can be established for the cancers that have mutated or activated Ras mutations, to inhibit the actions of the protein. The Raf protein has isoforms of A-Raf, B-Raf, and C-Raf that play three different functions [Biochim. Biophys. Acta., 2003, 1653, 25˜40]. Among these, B-Raf plays a key role in connecting the signaling from Ras to MEK. All these three Raf genes are expressed in most of the tissues. B-Raf and A-Raf are highly expressed in neural tissue and urogenital tissue, respectively. Each in the Raf family has a very similar amino acid sequence, but can be identified by biochemical activity and biological function [Exp. Cell. Res. 1999, 253, 34˜46]. According to the research results achieved so far, B-Raf is an important isoform protein related to cell proliferation and an important target of the oncogenic Ras. Abnormal mutations in the body have been confirmed only in the case of B-Raf, which are believed to occur in malignant cutaneous melanoma at an incidence rate of 30˜60% [Nature, 2002, 417, 949˜954], thyroid cancer at 30˜50%, colorectal cancer at 5˜20%, and ovarian cancer at 30% or less [Nature Rev. Mol. Cell Biology, 2004, 5, 875˜885]. Until now, 45 or more B-Raf mutations have been known. And among these mutations, the mutation from valine 600 into glutamic acid is most frequently observed in more than 90% of human cancers. This mutation is considered to increase the activity of B-Raf kinase and transmit the Raf/MEK/ERK signals to a downstream signaling pathway including the structural activity of ERK as a result of the activities of the Ras and growth factor receptors. The mutated B-Raf protein is transformed in NIH3T3 cells [Nature, 2002, 417, 949˜954] and melanophores [Cancer Res., 2004, 64, 2338˜2342], and is essential for the survival and transformation of melanoma [Cancer Res., 2003, 63, 5198˜5202]. Therefore, the B-Raf at the core of the serial signal transduction of Raf/MEK/ERK plays a vital role in the survival of tumors.
Accordingly, the inventors of the present invention completed the present invention as a result of the long-time researches on the inhibitor that can regulate the activity of B-Raf kinase, after synthesizing a novel purinylpyridinylamino-2,4-difluorophenyl sulfonamide derivative represented by Formula 1, which has a desirable activity against Raf kinase, and discovering that the derivative has a desirable effect on the diseases induced by the over-activity of Raf kinase.